Two-thirds of Americans are overweight or obese and around the world obesity rates are rising. A hallmark of obesity is elevated plasma leptin concentrations but a resistance to leptin signaling in the brain. Leptin circulates in the blood in proportion to the amount of white adipose tissue in the body. When food is readily- available, leptin signaling inhibits feeding and promotes energy expenditure. The resistance to leptin that occurs in diet-induced obesity is thought to be evolutionarily adaptive because it enables the accumulation of energy stores when food is readily-available, which presumably promotes survival during periods scarcity. The consequences of leptin-resistance once food becomes scarce are unclear. Evidence suggests that leptin promotes energy expenditure without inhibiting feeding when animals have access to a limited amount of food. Using homecage operant boxes, I found that mice that do not secrete leptin (ob/ob mice) overeat when food is relatively easy to obtain, but are less likely to seek food when it is relatively scarce. This suggests that leptin signaling promotes food-seeking when resources are scarce. I hypothesize that leptin's interaction with midbrain dopamine neurons is important for promoting food-seeking when the cost of acquiring it is relatively high. The dopamine system plays a critical role in feeding when work is required to obtain food. It has been shown that the absence of leptin signaling in the brain reduces intracellular dopamine production. I will test: 1) whether chronic leptin replacement in ob/ob mice restores food-seeking as scarcity increases;and 2) whether restoring dopamine production in the brain using systemic l-dopa injections restores food-seeking and/or energy expenditure as scarcity increases in ob/ob mice. To establish whether the ability of leptin to promote food-seeking is dependent on its direct effects on dopamine neurons, I will test whether leptin signaling in dopamine neurons is required for food-seeking as scarcity increases. I will induce leptin-resistance in dopamine neurons by employing a tissue-specific functional knockout of leptin receptors in dopamine neurons only. PUBLIC HEALTH RELEVANCE: Obesity is as much a behavioral disorder as it is a metabolic one. The origins of behaviors that promote weight gain in modern society - overconsumption and underactivity - are likely to be the product of brain-body interactions. Leptin, which is secreted from fat cells as they become larger and more numerous, is an important signal that conveys information about how much energy the body has stored. The goal of this project is to investigate whether leptin interacts with the brain's dopamine system to enhance motivation and energy expenditure, and prevent underactivity.